Typical Anatomy of the Upper Urinary System
The kidneys are organs that have numerous biological roles. Their primary role is to maintain the homeostatic balance of bodily fluids by filtering and secreting metabolites and minerals from the blood and excreting them, along with water, as urine. The ureters are muscular ducts that propel urine from the kidneys to the urinary bladder. In the adult, the ureters are usually 25-30 cm (10-12 inches) long.
The upper urinary system receives autonomic (mostly sympathetic) innervation, by the efferent nervous system. The sensory information is conveyed to the central nervous system (CNS) via the afferent nervous systems. The two systems have different regional distribution; the efferent sympathetic innervation reaches all the segments of the renal vasculature and to a much lesser extent the tubular nephron. The afferent sensory fibers are localized and predominate in the renal pelvis and ureter. The corticomedullary connective tissue contains both types of innervation with a more prominent afferent innervation.
Congestive Heart Failure
Congestive heart failure (CHF) is a very common disorder, affecting 6 million Americans and more than 22 million worldwide. CHF is a disease of the old; it is the leading hospital discharge diagnosis in individuals aged 65 years or older. CHF is the number one reason for hospitalization in people 65 years or older in the United States, accounting for approximately 1 million hospitalizations annually. The cost of hospitalizations for CHF is twice that for all forms of cancer and myocardial infarction combined. Treatment of heart failure costs an estimated $40 billion per year in the United States and nearly $80 billion worldwide.
The Cardio-Renal Syndrome
Renal impairment is an independent and significant predictor of morbidity and mortality in CHF patients. Mortality increases incrementally across the range of renal function, with 7% increased risk for every 10-mL/min decrease in glomerular filtration rate (GFR). CHF triggers kidney dysfunction by a pathological process dubbed the cardio-renal syndrome. The cardio-renal syndrome can be acute, characterized by a rapid decrease in cardiac output together with worsening renal function or chronic, in which gradual worsening of heart and/or kidney function develops over months.
The cardio-renal syndrome is a common condition; in the US, more than 500,000 patients are admitted to hospital every year with acute heart failure, and up 80% of these patients suffer from deteriorating renal functions. High renal sympathetic activity constitutes an important link between CHF and renal dysfunction. Signals of shock and hypoperfusion, present in CHF patients, activate a number of compensation systems to increase the blood pressure and prevent fluid losses. Of these, the renal sympathetic system is one of the most important ones; it effectively reduces renal blood flow and kidney functions, including sodium and water excretion to urine. In addition it activates the renin-angiotensin-aldosterone axis and therefore leads to hypertension, fluid retention and kidney dysfunction. It is now known that increased renal sympathetic drive is an independent factor in terms of progressive deterioration of renal function and adverse outcome in CHF patients as was shown by (Petersson et al., 2005).
The Current Treatment of CHF and the Cardio-Renal Syndrome
As of now, CHF is a progressive, incurable disease. Surgical treatment options are few and are reserved for end-stage patients.
In patients with CHF and volume overload, initial therapy focuses on salt and water restriction and diuretics. Diuretics improve symptoms and quality of life but do not necessarily prolong life. When patients experience persistent pulmonary congestion despite adequate diuretic treatment, they are defined as diuretic resistant. It is unadvised to increase the dose of the diuretic as the potential negative side effects outweigh the possible benefit of fluid removal. One of the most serious side effects of diuretic administration is activation of the renin-angiotensin-aldosterone axis and the sympathetic nervous system that leads to vasoconstriction and hypoperfusion.
Angiotensin-converting enzyme inhibitors (ACEI) and beta blockers are prescribed to most patients for control of hypertension and to reduce cardiac remodeling. Although ACEI and adrenergic blockers are extensively used in these patients, these agents work on a systemic level. As such they cannot be used in an adequate dosage to selectively inhibit the pathological sympathetic renal drive.
Hypertension
Hypertension is one of the most common worldwide diseases afflicting humans. In the US, forty-three million people are estimated to have hypertension, the age-adjusted prevalence of hypertension varying from 18-32%. Because of the associated morbidity and mortality and the cost to society, hypertension is an important public health challenge; hypertension is the most important modifiable risk factor for coronary heart disease (which is the leading cause of death in North America), stroke (the third leading cause), congestive heart failure, end-stage renal disease, and peripheral vascular disease.
Abnormal renal excretory function is one of the most important mechanisms of the initiation and progression of hypertension. Variations of arterial pressure signals the kidney to alter urinary sodium and water excretion. On the long term, maintenance of sodium and water balance by the kidneys is believed to be primary in the long-term control of arterial pressure. Thus, factors that decrease renal excretory function lead to an increase in arterial pressure, which is required to reestablish and maintain sodium and water balance.
The dramatic positive effect of renal denervation on the development of hypertension is evident in a wide variety of animal models in multiple species, suggesting that increased renal nerve activity may be a final common pathway for the defect in renal sodium excretory ability required for the development and maintenance of hypertension.
Chronic Kidney Disease
Chronic kidney disease (CKD) is a major cause of morbidity and mortality, particularly at the later stages. More than 400,000 patients (US) are on dialysis per year at an annual cost up to $67,000 for each patient. The 5-year survival rate for a patient undergoing chronic dialysis in the United States is approximately 35%. The most common cause of death in the dialysis population is cardiovascular disease.
A large body of evidence indicates the presence of functional abnormalities of the sympathetic nervous system in uremic animals and humans. In patients with bilateral nephrectomy, the rate of sympathetic discharge was lower than in patients with their native kidneys, and this increased rate was accompanied by lower mean arterial pressure and regional vascular resistance.
Sympathetic activation contributes to progressive kidney damage by elevation of blood pressure and by promoting atherosclerosis. Increased sympathetic activity, progressive atherosclerosis and elevated blood pressure contribute to the development of cardiac remodeling and functional alterations. These conditions are highly prevalent in patients with CKD.
Current treatment aims for CKD are to halt the progression of the renal damage by controlling the underlying condition that triggers the damage, i.e. hypertension and diabetes. Prescription of ACEI in such patients should take into account the potential influence of renal impairment on ACEI metabolism, and adverse effects on the renal function itself (especially hypotension and acute reductions in glomerular filtration rate which if untreated can escalate to acute renal failure).
Drugs that act on the sympathetic overactivity, such as alpha and beta adrenergic blockers are second or third line of treatment. These agents have significant side effects; alpha blockers were recently shown to increase the risk for stroke in patients with essential hypertension. Beta blockers are associated with intradyalitic hypotension.
As GFR decreases, diuretics are increasingly required for excretion of the daily water load. However, for a number of reasons diuretics become relatively ineffective in patients with a moderate to severe degree of chronic kidney disease (creatinine clearance below approximately 35 ml·min-1). Diuretics can lead to further rise in the serum creatinine and blood urea nitrogen concentrations and a high incidence of hypokalemia and electrolyte disorders. Furthermore, net losses of sodium and fluid during regular diuretic administration are limited by postdiuretic renal sodium and fluid retention. Because of these complications, diuretic use in the final stages of chronic kidney disease, although desirable theoretically to maintain body water balance is impractical because of the severe side effects
Acute Renal Failure
Causes of acute renal failure (ARF) can be broadly divided into three clinical categories: a) Prerenal, which is an adaptive response to severe volume depletion b) renal (or intrinsic), in response to kidney insult, including contrast material and c) postrenal.
Prerenal ARF is the most common cause of ARF. It often leads to intrinsic ARF if it is not promptly corrected. Acute reduction of renal blood flow (RBF), either because of blood loss or hypotension can result in this syndrome. The hallmark of intrinsic ARF and the most common form is acute tubular injury (ATN). Prerenal ARF and ATN occur on a continuum of the same pathophysiological process and together account for 75% of the cases of ARF.
It cannot be overstated that the current treatment of ARF is mainly supportive in nature and no therapeutic modalities to date have shown efficacy in treating the condition. Indications of immediate dialysis treatment include hyperkalemia not responsive to conventional treatment, pulmonary edema, and uremia.
Mortality rate estimates in ARF patients vary from 25-90%. The in-hospital mortality rate is 40-50%; in intensive care settings, the rate is 70-80%. The mortality in patients requiring dialysis is about 50%. Mortality rates have changed little over the last two decades, reflecting the fact that there is no adequate treatment for this condition.
The following patents and publication may relate to stimulation of the urinary system. Their disclosures are incorporated herein by reference. Some embodiments of the invention use apparatus described therein and/or processes and/or physiological effects described therein, with the appropriate changes, and/or in combination with methods and/or apparatus described herein, to provide functionality in accordance with some embodiments of the invention.
U.S. Patent Application Publications:
2005/0228459, 2005/0228460, 2005/0234523, 2005/0288730, 2006/0025821, 2006/0041277, 2006/0116720, 2006/0142801, 2006/0206150, 2006/0212076, 2006/0212078, 2006/0235474, 2006/0265014, 2006/0265015, 2006/0271111, 2006/0276852, 2007/0066957, 2007/0083239, 2007/0112327, 2007/0129760, 2007/0129761, 2007/0135875, 2007/0173899, 2007/0203549, 2007/0208382, 2007/0265687, 2007/0282184, 2008/0119907, 2008/0213331, 2008/0255642, 2009/0024195, 2009/0036948, 2009/0062873, 2009/0076409 and 2009/0221939.
U.S. Patents:
U.S. Pat. Nos. 5,749,845, 6,425,877, 6,500,158, 6,692,490, 6,699,216, 6,743,197, 6,978,174, 7,162,303, 7,326,235, 7,617,005 and 7,620,451.
Non-U.S. Patents and Publications:
RU 2004103992/14, RU 2271840 C2, WO 97/44088 and WO 2004/075948.
Other Publications:
Bakunts SA, Muradian KM (1977) Effect of electric stimulation on ureteral function. Zh Eksp Klin Med 17:8-15.
Bencsath P, Szenasi G, Asztalos B, Takacs L (1985) Time course of denervation diuresis and natriuresis in the anaesthetized rat. Acta Physiol Hung 66:47-50.
Blair JE, Khan S, Konstam MA, Swedberg K, Zannad F, Burnett JC, Jr., Grinfeld L, Maggioni AP, Udelson JE, Zimmer CA, Ouyang J, Chen CF, Gheorghiade M (2009) Weight changes after hospitalization for worsening heart failure and subsequent re-hospitalization and mortality in the EVEREST trial. Eur Heart J 30:1666-1673.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816-824.
Chen SS, Chen WC, Hayakawa S, Li P C, Chien CT (2009) Acute urinary bladder distension triggers ICAM-1-mediated renal oxidative injury via the norepinephrine-renin-angiotensin II system in rats. J Formos Med Assoc 108:627-635.
Chien CT, Yu HJ, Cheng YJ, Wu MS, Chen CF, Hsu SM (2000) Reduction in renal haemodynamics by exaggerated vesicovascular reflex in rats with acute urinary retention. J Physiol 526 Pt 2:397-408.
Chuang YC, Fraser MO, Yu Y, Beckel JM, Seki S, Nakanishi Y, Yokoyama H, Chancellor MB, Yoshimura N, de Groat WC (2001) Analysis of the afferent limb of the vesicovascular reflex using neurotoxins, resiniferatoxin and capsaicin. Am J Physiol Regul Integr Comp Physiol 281:R1302-1310.
De Bock F, De Wachter S, Wyndaele JJ (2009) Can the use of different parameters and waveforms improve the results of intravesical electrical stimulation: a pilot study in the rat. Neurourol Urodyn 28:246-250.
Deng PY, Li YJ (2005) Calcitonin gene-related peptide and hypertension. Peptides 26:1676-1685.
Derzhavin VM, Vishnevskii EL, Dzheribal'di OA, Bruk SD, Vasil'ev AI (1989) Electric stimulation of the ureterovesical anastomosis in the treatment of hyperreflexia of the urinary bladder. Pediatriia: 53-57.
DiBona GF (2004) The sympathetic nervous system and hypertension: recent developments. Hypertension 43:147-150.
DiBona GF, Kopp UC (1997) Neural control of renal function. Physiol Rev 77:75-197.
DiBona GF, Sawin LL (1999) Renal hemodynamic effects of activation of specific renal sympathetic nerve fiber groups. Am J Physiol 276:R539-549.
Dwyer TM, Schmidt-Nielsen B (2003) The renal pelvis: machinery that concentrates urine in the papilla. News Physiol Sci 18:1-6.
Fagius J, Karhuvaara S (1989) Sympathetic activity and blood pressure increases with bladder distension in humans. Hypertension 14:511-517.
Gardiner SM, Compton AM, Kemp PA, Bennett T, Foulkes R, Hughes B (1991) Regional haemodynamic effects of prolonged infusions of human alpha-calcitonin gene-related peptide in conscious, Long Evans rats. Br J Pharmacol 103:1509-1514.
Gotloib L, Fudin R, Yakubovich M, Vienken J (2005) Peritoneal dialysis in refractory end-stage congestive heart failure: a challenge facing a no-win situation. Nephrol Dial Transplant 20 Suppl 7:vii32-36.
Jiang CH, Lindstrom S (1999) Prolonged enhancement of the micturition reflex in the cat by repetitive stimulation of bladder afferents. J Physiol 517 (Pt 2):599-605.
Kenton K, Simmons J, FitzGerald M P, Lowenstein L, Brubaker L (2007) Urethral and bladder current perception thresholds: normative data in women. J Urol 178:189-192; discussion 192.
Kolesnikow GP, Karpenko WS (1987) Development and assessment of an artificial pacemaker of the ureter with feedback. Z Urol Nephrol 80:25-29.
Kopp UC, Smith LA (1987) Renorenal reflex responses to renal sensory receptor stimulation in normotension and hypertension. Clin Exp Hypertens A 9 Suppl 1:113-125.
Kopp UC, Olson LA, DiBona GF (1984) Renorenal reflex responses to mechano- and chemoreceptor stimulation in the dog and rat. Am J Physiol 246:F67-77.
Kopp UC, Jones SY, DiBona GF (2008) Afferent renal denervation impairs baroreflex control of efferent renal sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol 295:R1882-1890.
Lang RJ, Davidson ME, Exintaris B (2002) Pyeloureteral motility and ureteral peristalsis: essential role of sensory nerves and endogenous prostaglandins. Exp Physiol 87:129-146.
Lazzeri M, Barbanti G, Beneforti P, Maggi CA, Taddei I, Andrea U, Cantini C, Castellani S, Turini D (1995) Vesical-renal reflex: diuresis and natriuresis activated by intravesical capsaicin. Scand J Urol Nephrol 29:39-43.
Li J, Wang DH (2008) Increased GFR and renal excretory function by activation of TRPV1 in the isolated perfused kidney. Pharmacol Res 57:239-246.
Ma MC, Huang H S, Chen CF (2002) Impaired renal sensory responses after unilateral ureteral obstruction in the rat. J Am Soc Nephrol 13:1008-1016.
Ma MC, Huang H S, Chen YS, Lee SH (2008) Mechanosensitive N-methyl-D-aspartate receptors contribute to sensory activation in the rat renal pelvis. Hypertension 52:938-944.
Melick WF, Brodeur AE, Herbig F, Naryka JJ (1966) Use of a ureteral pacemaker in the treatment of ureteral reflux. J Urol 95:184-196.
Ming Z, Smyth DD, Lautt WW (2002) Decreases in portal flow trigger a hepatorenal reflex to inhibit renal sodium and water excretion in rats: role of adenosine. Hepatology 35:167-175.
Palla R, Parrini M, Panichi V, Andreini B, De Pietro S, Migliori M, Bianchi AM, Giovannini L, Bertelli A, Bertelli AA, et al. (1995) Acute effects of calcitonin gene related peptide on renal haemodynamics and renin and angiotensin II secretion in patients with renal disease. Int J Tissue React 17:43-49.
Petersson M, Friberg P, Eisenhofer G, Lambert G, Rundqvist B (2005) Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure. Eur Heart J 26:906-913.
Petkov P (1975) Electrostimulation of the ureter as a treatment method in ureteral calculi. Khirurgiia (Sofia) 28:292-294.
Polsky A, Mel B, Schiller J (2009) Encoding and decoding bursts by NMDA spikes in basal dendrites of layer 5 pyramidal neurons. J Neurosci 29:11891-11903.
Ronco C, Chionh CY, Haapio M, Anavekar NS, House A, Bellomo R (2009) The cardiorenal syndrome. Blood Purif 27:114-126.
Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD (2009) Renal Denervation as a Therapeutic Approach for Hypertension: Novel Implications for an Old Concept. Hypertension 54:1195-1201.
Schramm LP, Carlson DE (1975) Inhibition of renal vasoconstriction by elevated ureteral pressure. Am J Physiol 228:1126-1133.
Shekhar YC, Anand IS, Sarma R, Ferrari R, Wahi PL, Poole-Wilson PA (1991) Effects of prolonged infusion of human alpha calcitonin gene-related peptide on hemodynamics, renal blood flow
Tsuchida S, Kumagai I (1978) Effect of urinary bladder distension on renal blood flow, blood pressure and plasma renin activity. Tohoku J Exp Med 126:335-341.
van Balken MR, Vergunst H, Bemelmans BL (2004) The use of electrical devices for the treatment of bladder dysfunction: a review of methods. J Urol 172:846-851.
Xie C, Sachs JR, Wang DH (2008) Interdependent regulation of afferent renal nerve activity and renal function: role of transient receptor potential vanilloid type 1, neurokinin 1, and calcitonin gene-related peptide receptors. J Pharmacol Exp Ther 325:751-757.
Zhu Y, Wang Y, Wang DH (2005) Diuresis and natriuresis caused by activation of VR1-positive sensory nerves in renal pelvis of rats. Hypertension 46:992-997.
Zhu Y, Xie C, Wang DH (2007) TRPV1-mediated diuresis and natriuresis induced by hypertonic saline perfusion of the renal pelvis. Am J Nephrol 27:530-537.